Nipah virus (NiV) and Hendra virus (HeV) are newly emergent zoonotic viruses that currently comprise their own genus, Henipavirus, within the family Paramyxoviridae. Paramyxoviruses are negative-sense RNA enveloped viruses and encompass a variety of important human and animal pathogens, including measles virus, mumps virus, Sendai virus, Newcastle disease virus, rinderpest virus, canine distemper virus, human parainfluenza viruses, respiratory syncytial virus, and simian virus 5 (reviewed in Lamb and Parks (2007) Fields Virology, eds. Knippe & Howley, Lippincott, Williams & Wilkins, pp. 1449-1496) The broad species tropisms of the Henipaviruses and the ability to cause fatal disease in both animals and humans distinguish HeV and NiV from all other known paramyxoviruses (reviewed in Eaton (2001) Microbes Infect 3:277-278). HeV and NiV are both regarded as Biological Safety Level-4 (BSL-4) pathogens, and are on the NIAID Biodefense research agenda as zoonotic emerging category C priority pathogens that could potentially be used as agents for bio-terrorism. Henipaviruses can be readily amplified in host livestock and can further cause disease in large animals. Henipaviruses can be aerosol transmitted to humans where disease may manifest as severe respiratory illness and febrile encephalitis. Human to human transmission is also possible. Henipaviruses can be readily grown in either cell culture or embryonated chicken eggs, can be produced in high un-concentrated titers (˜108 TCID50/ml), and can be highly infectious (Crameri et al. (2002) J. Virol. Methods 99:41-51; Field et al. (2001) Microbes Infect. 3:307-314; Hooper et al. (2001) Microbes Infect 3:315-322).
The principal reservoirs for both NiV and HeV appear to be several species of pteroid fruit bats, common to Southeast Asia and the Pacific, and hence most reported viral outbreaks seen to date have been in those areas (Eaton et al. (2006) Nat. Rev. Microbiol. 4:23-35). HeV first appeared in Australia in 1994 in two unrelated but similarly timed episodes of severe respiratory disease in horses, in which a total of three transmissions to humans were observed, two of which resulted in death. HeV reemerged through fatal equine infections in Australia in 1999, 2004, and 2006 (Field et al. (2000) Aust. Vet J. 78:279-280; Anonymous (2004) Int. Soc. for Infect. Dis. 20041214.3307; Murray (2006) World Org. for Animal Health Vol. 19-No. 26). NiV emerged in between 1997 and 1998 in an outbreak of encephalitis among pig farmers in both Malaysia and Singapore, generating 265 reports of human infection, of which 105 were fatal (Chua (2003) J. Clin. Virol. 26:265-275). NiV recently reemerged in Bangladesh. Two outbreaks of NiV occurred in 2004, and yet another in January of 2005 (Communicable Disease Report Weekly (2005) Vol. 15 No. 16). Several important observations in the more recent outbreaks have been made, including higher incidence of acute respiratory distress syndrome, person-to-person transmission, and significantly higher case fatality rates (approaching 75%) (Health and Science Bulletin (2004) 2:5-11; Hsu et al. (2004) Emerg. Infect. Dis. 10:2082-2087).
Physiologically, paramyxoviruses possess two major membrane-anchored glycoproteins in the envelope of the viral particle that are required for infection of a receptive host cell. The two glycoproteins serve different but complementary functions. One glycoprotein acts to achieve physical attachment with the host while the other glycoprotein acts to achieve effective fusion with the host. Typically, without the concerted action of both, the host cannot be infected.
The attachment glycoprotein is a type II membrane protein where the amino (N-) terminus is oriented toward the cytoplasm and the carboxy (C-) terminus is on the other side of the plasma membrane and in the extracellular material. The attachment glycoprotein can be either a hemagglutinin-neuraminidase protein (HN), a hemagglutinin protein (H), or a glycoprotein (G) (which lacks hemagglutination and neuraminidase activities) depending on the particular virus (reviewed in Lamb & Parks (2007) Fields Virology, eds. Knippe & Howley, Lippincott Williams & Wilkins, pp. 1449-1496). Traditionally, the HN, H, and G proteins are the principal antigens to which virtually all neutralizing antibodies are directed. NiV and HeV both express G glycoproteins. Previous studies focusing on the G glycoproteins from NiV and HeV have yielded effective subunit vaccines and diagnostic reagents. The primary function of the paramyxovirus attachment glycoprotein is to engage appropriate receptors on the surfaces of host cells, which for the majority of well-characterized paramyxoviruses, are sialic acid moieties. HeV and NiV glycoprotein, however, utilizes the host cell protein receptors ephrinB2 and/or ephrinB3 (Bishop et al. (2007) J. Virol. 81:5893-5901; Bonaparte et al. (2005) Proc. Natl. Acad. Sci. U.S.A. 102: 10652-10657; Negrete et al. (2006) PLoS Pathog 2: e7).
The fusion (F) glycoprotein in paramyxoviruses mediates pH-independent membrane fusion between the virus and its host cell, which results in delivery of the nucleocapsid. Paramyxovirus F glycoproteins are trimeric class I fusogenic envelope glycoproteins, with the protein's N-terminus being located in the extracellular domain. An important feature of paramyxovirus F glycoproteins is the presence of two heptad repeat regions and a hydrophobic fusion peptide. HeV and NiV infect through a pH-independent membrane fusion process into the host cell by the concerted action of the attachment and fusion glycoproteins. In nearly all cases, both glycoproteins are required for efficient membrane fusion (Bossart & Broder (2007) Viral Entry into Host Cells, eds. Pohlmann & Simmons, Landes Bioscience).
Upon activation of the fusion mechanism, F glycoproteins will undergo conformational changes that facilitate the insertion of the fusion peptide into target membranes. The conformational changes bring the two heptad repeat regions together for the formation of a six-helix bundle structure (also called a timer-of-hairpins). These conformational changes occur during or immediately following virus-cell membrane fusion reviewed in Lamb et al. (2006) Virology 344:30-37). Several molecular details of the substantial conformational change of F glycoprotein have been revealed in the recent structural solutions of both post- and pre-fusion conformations of F glycoprotein (Yin et al. (2005) Proc. Natl. Acad. Sci. U.S.A. 102:9288-9293; Yin et al. (2006) Nature 439:38-44).
Research in Henipaviruses is of extreme importance for at least two major reasons: to gain insight into the physiology of these viruses, and to develop strategies to treat, to detect and to prevent their further outbreak. Currently, therapeutics and methodologies for diagnosis for NiV- or HeV-infected individuals are limited. Given the novelty and threat posed by these viruses, there is a need for improved means of treating and/or preventing an infection by NiV or HeV, as well as a means for accurately detecting an infection.